Genetic factors involved in the acute respiratory distress syndromefrom animal models to patient studies

  1. Marialbert Acosta Herrera
Supervised by:
  1. Carlos Alberto Flores Infante Director
  2. Jesús Villar Hernández Director

Defence university: Universidad de La Laguna

Year of defence: 2015

Committee:
  1. Hortense Slevogt Chair
  2. Mariano Hernández Ferrer Secretary
  3. J. Blanco Committee member

Type: Thesis

Teseo: 394111 DIALNET

Abstract

The acute respiratory distress syndrome (ARDS) is a severe inflammatory disease manifested as a result of pulmonary and systemic responses to several insults. It is well accepted that genetic variation influences these responses. However, little is known about the genes and pathways that are responsible for patient susceptibility, outcome and follow up in ARDS. This doctoral thesis shows four major blocks of results. In the first block, we performed a systematic overview of the methodology applied in genetic association studies in acute respiratory distress syndrome (ARDS), and evaluated the state of the art in the field, highlighting the associated gene variants and recognizing critical methodological limitations that are still present in the literature. The second and third blocks correspond to genetic association studies in two candidate genes: NFE2L2 and WNT5A in patients with severe sepsis. The biological plausibility of these two genes is well supported in the scientific literature. In the case of the NFE2L2 gene, functional evidences reinforced the association of one variant that was previously associated with ARDS in patients with severe trauma. Regarding the WNT5A gene, the results were supported by previous functional evidences showing that the protein encoded by this gene is elevated in animal models of sepsis and ventilator-induced lung injury. The fourth block corresponds to a transcriptomic study in an animal model of lung injury developed after sepsis. By utilizing several bioinformatic tools and after several cross-species validation in publicly available human transcriptomic and genomic studies and microRNA (miRNA) sequencing, this thesis shows a new process, never anticipated in the syndrome, involved in lung repair modulated by low tidal volume mechanical ventilation, which is the only lung support applied to patients suffering from ARDS.